The goal of this proposal is to evaluate potential motor function deficits and cognitive impairments in a series of BAC-mediated transgenic mice, which over-express mutant LRRK2 carrying Parkinson's disease (PD)-linked familial mutation. PD is characterized primarily by the deficits in motor function in the CNS. Recently, non-motor symptoms including cognitive impairments have been increasingly recognized as important manifestations of neuropathology in PD. However, no animal models are currently available that recapitulate PD symptoms including motor and non- motor impairments. Missense mutations in LRRK2 (Leucine-Rich Repeat Kinase 2) or PARK8 have recently been linked to the most common familial forms as well as some sporadic forms of PD. We recently established transgenic mice over-expressing LRRK2 wild-type (WT), PD-linked mutant G2019S or R1441G by using bacterial artificial chromosome (BAC)-mediated transgenic approach, which utilizes endogenous promoter and necessary regulatory elements for the proper expression of LRRK2 in the mouse brains. These BAC-transgenic mice provide us with valuable tools to specifically characterize potential hyper-activated pathways mediated by LRRK2 in the pathogenesis of PD. In our proteomic study of LRRK2-binding proteins in the brain, we found that LRRK2 interacts with proteins that are associated with synaptic membrane or regulation of synaptic plasticity. Recent study also indicates that LRRK2 is expressed at high levels in the cortex, hippocampus and amygdala that serve cognitive functions. Since the impaired synaptic functions in these areas are frequently linked to the cognitive deficits, it raises the possibility that over-expression of PD-linked mutants of LRRK2 may alter the synaptic activity and plasticity, which in turn may perturb the cognitive execution. Thus, we propose to assess the motor functions as well as to investigate non-motor complications in LRRK2 transgenic mice, It will be of critical importance to know (1) Whether LRRK2 transgenic mice display motor function deficits, (2) whether non-motor manifestations including cognitive deficits develop in the LRRK2 transgenic mice, and (3) whether the onset of the non-motor symptoms precede the motor dysfunction. Hence this study will explore these models to determine the role of LRRK2 in motor functions and its potential interaction or coordination with cognitive functions. PUBLIC HEALTH RELEVANCE: The pathological symptoms of Parkinson's disease include motor deficits as well as non-motor impairments. This project is to investigate motor function and non- motor complications (e.g. cognitive dysfunctions) in Parkinson's disease by using novel transgenic approach. We will conduct behavioral and electrophysiological characterizations of the established transgenic animals expressing gene mutations which are linked to the Parkinson's disease. This study is expected to provide insight into the neurobiology for Parkinson's disease.